Publications by authors named "Yusuke Imamura"

46 Publications

Successful treatment of metastatic bladder cancer by gemcitabine-cisplatin re-challenge after pembrolizumab.

IJU Case Rep 2021 Nov 20;4(6):360-362. Epub 2021 Jul 20.

Department of Urology Chiba University Graduate School of Medicine Chiba Japan.

Introduction: The advent of pembrolizumab has contributed to improved treatment outcomes for metastatic urothelial carcinoma, but the outcomes of treatments after second-line treatment have not been established.

Case Presentation: A 72-year-old man was referred to our hospital with gross hematuria and diagnosed with suspicion of bladder cancer cT1N0M0. Transurethral resection of the bladder tumor was performed, but local recurrence and multiple lung metastases appeared 5 months after surgery. Although gemcitabine-cisplatin was performed as first-line chemotherapy, the local lesion increased, and pembrolizumab was used as a second-line treatment. Pembrolizumab was also ineffective; however, re-challenge with gemcitabine-cisplatin as third-line treatment produced a good therapeutic effect.

Conclusion: We report a successful case in which gemcitabine-cisplatin re-challenge after pembrolizumab therapy was effective in metastatic bladder cancer. Re-administration of chemotherapy after immune checkpoint inhibitors may be a broadly effective treatment option.
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http://dx.doi.org/10.1002/iju5.12348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560445PMC
November 2021

Expression of tertiary lymphoid structure in deferred cytoreductive nephrectomy of metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

IJU Case Rep 2021 Nov 16;4(6):355-358. Epub 2021 Aug 16.

Urology Graduate School of Medicine Chiba University Chiba Japan.

Introduction: Tertiary lymphoid structure expression and immune checkpoint inhibitors have been attracting attention, and their relationship with renal cell carcinoma is controversial.

Case Presentation: Two patients with nivolumab plus ipilimumab treatment response for metastatic renal cell carcinoma underwent cytoreductive nephrectomy and regional lymph node dissection. In both cases, the renal tumor site expressed tertiary lymphoid structures. Despite the absence of treatment after a deferred cytoreductive nephrectomy and the short postoperative observation period, the patients still survived.

Conclusion: Tertiary lymphoid structures were expressed in deferred cytoreductive nephrectomy specimen in cases treated with nivolumab plus ipilimumab.
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http://dx.doi.org/10.1002/iju5.12347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560443PMC
November 2021

Dermatomyositis-related interstitial lung disease mimicking COVID-19 pneumonia.

Cleve Clin J Med 2021 09 1;88(9):484-486. Epub 2021 Sep 1.

Department of Rheumatology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan.

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http://dx.doi.org/10.3949/ccjm.88a.20204DOI Listing
September 2021

The heavy chain of 4F2 antigen promote prostate cancer progression via SKP-2.

Sci Rep 2021 06 1;11(1):11478. Epub 2021 Jun 1.

Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan.

The 4F2 cell-surface antigen heavy chain (4F2hc) forms a heterodimeric complex with L-type amino acid transporter 1 (LAT1) and transports large neutral essential amino acids. However, in contrast to the traditional role of LAT1 in various cancers, the role of 4F2hc has largely remained unknown. The role of 4F2hc in prostate cancer was studied. Treatment of C4-2 cells with si4F2hc was found to suppress cellular growth, migratory and invasive abilities, with this effect occurring through the cell cycle, with a significant decrease in S phase and a significant increase in G0/G1 phase, suggesting cell cycle arrest. In addition, it was proven by RNA seq that the key to 4F2hc's impact on cancer is SKP2. si4F2hc upregulates the protein expression of cyclin-dependent kinase inhibitors (P21cip1, P27kip1) through the downstream target SKP2. Furthermore, the expression of 4F2hc and LAT1 in prostate cancer cells suggests the importance of 4F2hc. Multivariate analysis showed that high 4F2hc expression was an independent prognostic factor for progression-free survival (HR 11.54, p = 0.0357). High 4F2hc was related to the clinical tumour stage (p = 0.0255) and Gleason score (p = 0.0035). Collectively, 4F2hc contributed significantly to prostate cancer (PC) progression. 4F2hc may be a novel marker and therapeutic target in PC.
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http://dx.doi.org/10.1038/s41598-021-90748-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169706PMC
June 2021

Functional analysis of LAT3 in prostate cancer: Its downstream target and relationship with androgen receptor.

Cancer Sci 2021 Sep 8;112(9):3871-3883. Epub 2021 Jul 8.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

L-type amino acid transporter 3 (LAT3, SLC43A1) is abundantly expressed in prostate cancer (PC) and is thought to play an essential role in PC progression through the cellular uptake of essential amino acids. Here, we analyzed the expression, function, and downstream target of LAT3 in PC. LAT3 was highly expressed in PC cells expressing androgen receptor (AR), and its expression was increased by dihydrotestosterone treatment and decreased by bicalutamide treatment. In chromatin immunoprecipitation sequencing of AR, binding of AR to the SLC43A1 region was increased by dihydrotestosterone stimulation. Knockdown of LAT3 inhibited cell proliferation, migration, and invasion, and the phosphorylation of p70S6K and 4EBP-1. Separase (ESPL1) was identified as a downstream target of LAT3 by RNA sequencing analysis. In addition, immunostaining of prostatectomy specimens was performed. In the multivariate analysis, high expression of LAT3 was an independent prognostic factor for recurrence-free survival (hazard ratio: 3.24; P = .0018). High LAT3 expression was correlated with the pathological T stage and a high International Society of Urological Pathology grade. In summary, our results suggest that LAT3 plays an important role in the progression of PC.
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http://dx.doi.org/10.1111/cas.14991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409400PMC
September 2021

[Patch Repair by Anterolateral Thoracotomy with Partial Sternotomy for Saccular Aortic Arch Aneurysm with Severe Thoracic Deformity:Report of a Case].

Kyobu Geka 2021 Feb;74(2):147-151

Department of Cardiovascular Surgery, Yokosuka Municipal Uwamachi Hospital, Yokosuka, Japan.

An 87-year-old male was referred to our hospital for surgery of saccular aortic arch aneurysm. As he had a history of thoracoplasty on his left side due to pulmonary tuberculosis, his aortic arch adhered to the apex of the left thorax. Total arch replacement(TAR) via median sternotomy was considered difficult, and anterolateral thoracotomy with partial sternotomy (ALPS) was performed. During surgery, we considered TAR difficult even with ALPS approach. Taking account of his age, aneurysmectomy and patch repair were chosen instead of TAR to shorten operation time. Although he suffered from diffuse cerebral infarction, he was discharged without neurological deficit at 39 days after operation.
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February 2021

Characteristics of benign adrenocortical adenomas with 18F-FDG PET accumulation.

Eur J Endocrinol 2021 Jun 5;185(1):155-165. Epub 2021 Jun 5.

Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Introduction: Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated.

Methods: To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers).

Results: All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation.

Discussion: A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation.

Conclusion: Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.
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http://dx.doi.org/10.1530/EJE-20-1459DOI Listing
June 2021

Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor.

Commun Biol 2021 03 22;4(1):381. Epub 2021 Mar 22.

Department of Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.

Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.
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http://dx.doi.org/10.1038/s42003-021-01927-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985297PMC
March 2021

Prognostic Value of High-Sensitivity Modified Glasgow Prognostic Score in Castration-Resistant Prostate Cancer Patients Who Received Docetaxel.

Cancers (Basel) 2021 Feb 12;13(4). Epub 2021 Feb 12.

Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.

The Glasgow prognostic score, a marker of systemic inflammation, is associated with clinical outcomes in different cancers including prostate cancer. However, there is no evidence for the relationship between the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) in prostate cancer and its prognosis. This study aimed to investigate the prognostic significance of Hs-mGPS in castration-resistant prostate cancer (CRPC) treated with docetaxel. We retrospectively analyzed clinical datasets from 131 CRPC patients who received docetaxel treatment at Chiba University Hospital and a related hospital. Clinical factors including Hs-mGPS before docetaxel treatment were evaluated according to overall survival. The numbers of patients with Hs-mGPS of 0, 1, and 2 were 88, 30, and 13, respectively. The median prostate-specific antigen (PSA) level was 28.9 ng/mL. The median testosterone level was 13.0 ng/dL. The percentages of bone and visceral metastases were 80.8% and 10.2%, respectively. For overall survival, Hs-mGPS ≥ 1 (hazard ratio of 2.41; = 0.0048), testosterone ≥ 13.0 ng/dL (hazard ratio of 2.23; = 0.0117), and PSA ≥ 28.9 ng/mL (hazard ratio of 2.36; = 0.0097) were significant poor prognostic factors in the multivariate analysis. The results of the two-group analysis showed that a higher Hs-mGPS was associated with high PSA, alkaline phosphatase, and testosterone levels. The median testosterone levels for Hs-mGPS of 0, 1, and 2 were 9.0, 16.5, and 23.0, respectively. Based on the multivariate analysis, we created a combined score with three prognostic factors: Hs-mGPS, testosterone, and PSA. The low-risk group (score of 0-1) showed a significantly longer overall survival compared to the intermediate-risk (score of 2-3) and high-risk (score of 4) groups ( < 0.0001). Our results demonstrated that an elevated Hs-mGPS was an independent prognostic factor in CRPC patients treated with docetaxel therapy. Risk classification based on Hs-mGPS, testosterone, and PSA may be useful in predicting the prognosis of CRPC patients.
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http://dx.doi.org/10.3390/cancers13040773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918602PMC
February 2021

[A case of sudden-onset transverse myelopathy suspected to be caused by fibrocartilaginous embolism].

Rinsho Shinkeigaku 2021 Jan 15;61(1):33-38. Epub 2020 Dec 15.

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University.

A 44-year-old male was admitted to our hospital because of sudden weakness and sensory loss in both legs following left scapular pain. He had a history of lower back pain but no vascular risk factors. Neurological examination on admission revealed flaccid paraplegia, a loss of both pinprick and vibratory sensations below the Th6 level, and bladder and rectal disturbances. Tendon reflexes were absent in both lower limbs. Diffusion-weighted imaging performed 5 hours after onset revealed an extensive high-intensity lesion at the Th2-6 spine levels, accompanied by a vague high intensity on T-weighted images. CT angiography showed no abnormalities of the aorta or the artery of Adamkiewicz. Laboratory test results were normal and there was no evidence of coagulopathy. Autoantibodies, including anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies, were negative. The cerebrospinal fluid test was normal. The lesion had expanded to the whole thoracic cord and was markedly swollen on T-weighted imaging at 5 days after onset. Immunotherapies, including intravenous methylprednisolone pulse therapy and plasma exchange, were ineffective. Although there was no evidence of any source of embolism, we found degenerative calcified changes in the fibrocartilage of the intervertebral discs, with Schmorl's nodes in the thoracic spines. We clinically diagnosed the patient with spinal cord infarction caused by fibrocartilaginous embolism. He developed deep vein thrombosis and was treated with edoxaban. His neurological symptoms did not improve during 55 days of hospitalization. In a case with sudden-onset myelopathy, fibrocartilaginous embolism should be considered.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001520DOI Listing
January 2021

Adrenalectomy in Japanese patients with subclinical Cushing syndrome: 1-mg dexamethasone suppression test to predict the surgical benefit.

Int J Urol 2021 03 30;28(3):273-279. Epub 2020 Nov 30.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

Objectives: To investigate whether the result of the 1-mg dexamethasone suppression test can predict the improvement of comorbidities after adrenalectomy in patients with subclinical Cushing syndrome.

Methods: This retrospective study included 117 subclinical Cushing syndrome patients who underwent adrenalectomy. The numbers of prescribed drugs for metabolic comorbidities and the clinical variables at diagnosis were compared with those at the follow up. Patients were classified into subgroups according to the result of the 1-mg dexamethasone suppression test.

Results: Significant improvements in blood pressure, serum cholesterol and body mass index were observed. Furthermore, a significant improvement in glycated hemoglobin was observed in patients with diabetes mellitus. These improvements led to a discontinuation or reduction of prescribed drugs after surgery. In addition, the greatest reduction of prescribed drugs was observed in patients whose serum cortisol levels were between 1.8 and 3.0 µg/dL after the 1-mg dexamethasone suppression test.

Conclusions: The result of the 1-mg dexamethasone suppression test can be a useful factor predicting the improvement of comorbidities after adrenalectomy. Current data might give us a new insight into the decision-making for the treatment of subclinical Cushing syndrome.
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http://dx.doi.org/10.1111/iju.14445DOI Listing
March 2021

Epigenetic modifications in prostate cancer.

Int J Urol 2021 02 27;28(2):140-149. Epub 2020 Oct 27.

Department of, Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan.

Prostate cancer is a major cause of cancer-related deaths among men worldwide. In addition to genomic alterations, epigenetic alterations accumulated in prostate cancer have been elucidated. While aberrant deoxyribonucleic acid hypermethylation in promoter CpG islands inactivates crucial genes associated with deoxyribonucleic acid repair, cell cycle, apoptosis or cell adhesion, aberrant deoxyribonucleic acid hypomethylation can lead to oncogene activation. Acetylation of histone is also deregulated in prostate cancer, which could cause aberrant super-enhancer formation and activation of genes associated with cancer development. Deregulations of histone methylation, such as an increase of trimethylation at position 27 of histone H3 by enhancer of zeste homolog2 overexpression, or other modifications, such as phosphorylation and ubiquitination, are also involved in prostate cancer development, and inhibitors targeting these epigenomic aberrations might be novel therapeutic strategies. In this review, we provide an overview of epigenetic alterations in the development and progression of prostate cancer, focusing on deoxyribonucleic acid methylation and histone modifications.
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http://dx.doi.org/10.1111/iju.14406DOI Listing
February 2021

Identification of AR-V7 downstream genes commonly targeted by AR/AR-V7 and specifically targeted by AR-V7 in castration resistant prostate cancer.

Transl Oncol 2021 Jan 20;14(1):100915. Epub 2020 Oct 20.

Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan. Electronic address:

Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) under androgen deprivation therapy, by mechanisms e.g. expression of androgen receptor (AR) splice variant-7 (AR-V7). Here we conducted comprehensive epigenome and transcriptome analyses comparing LNCaP, primary PC cells, and LNCaP95, AR-V7-expressing CRPC cells derived from LNCaP. Of 399 AR-V7 target regions identified through ChIP-seq analysis, 377 could be commonly targeted by hormone-stimulated AR, and 22 were specifically targeted by AR-V7. Among genes neighboring to these AR-V7 target regions, 78 genes were highly expressed in LNCaP95, while AR-V7 knockdown led to significant repression of these genes and suppression of growth of LNCaP95. Of the 78 AR-V7 target genes, 74 were common AR/AR-V7 target genes and 4 were specific AR-V7 target genes; their most suppressed genes by AR-V7 knockdown were NUP210 and SLC3A2, respectively, and underwent subsequent analyses. NUP210 and SLC3A2 were significantly upregulated in clinical CRPC tissues, and their knockdown resulted in significant suppression of cellular growth of LNCaP95 through apoptosis and growth arrest. Collectively, AR-V7 contributes to CRPC proliferation by activating both common AR/AR-V7 target and specific AR-V7 target, e.g. NUP210 and SLC3A2.
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http://dx.doi.org/10.1016/j.tranon.2020.100915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581977PMC
January 2021

Relationship between post-void residual urine volume, preoperative pyuria and intravesical recurrence after transurethral resection of bladder carcinoma.

Int J Urol 2020 Nov 1;27(11):1024-1030. Epub 2020 Sep 1.

Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Objectives: To evaluate the relationship between residual urine volume, pyuria and bladder carcinoma recurrence.

Methods: The clinical data of 305 patients who had post-void residual urine volume measured and preoperative pyuria were retrospectively collected. The patients were classified into three risk groups based on the presence of residual urine and pyuria: good (negative residual urine and pyuria), intermediate (positive residual urine or pyuria) and poor (positive residual urine and pyuria). Predictive factors for intravesical recurrence-free survival were statistically analyzed using Cox proportional hazard models and Kaplan-Meier methods. The propensity score matching method was used to adjust the patients' backgrounds.

Results: The median follow-up period for all patients was 44 months. The presence of residual urine (P = 0.0164) and pyuria (P = 0.0233) were two independent prognostic factors for recurrence. After patients were classified into risk groups, the poor-risk group showed significantly shorter recurrence-free survival compared with that of the good- (P = 0.0002) and intermediate-risk groups (P = 0.0090). Even after matching, the presence of residual urine was related to short recurrence-free survival in male patients (P = 0.0012). When stratified by European Organization for Research and Treatment of Cancer risk groups, the presence of pyuria was related to short recurrence-free survival, especially for intermediate-risk patients without bacillus Calmette-Guérin treatment.

Conclusions: Post-void residual urine and preoperative pyuria are two risks for recurrence-free survival in non-muscle-invasive bladder cancer.
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http://dx.doi.org/10.1111/iju.14352DOI Listing
November 2020

Left ileal conduit: A case report.

IJU Case Rep 2020 Mar 11;3(2):33-35. Epub 2019 Dec 11.

Department of Urology Chiba University Hospital Chiba Japan.

Introduction: When ileal conduit construction is performed for urinary tract drainage during radical cystectomy, the conduit is usually constructed in the right lower abdomen. However, no reports have described ileal conduit construction in the left lower abdomen when it cannot be performed on the right side. In addition, some ingenuity is necessary for construction on the left.

Case Presentation: A 75-year-old woman visited our hospital with chief complaint of gross hematuria. Computed tomography and cystoscopy showed a huge bladder tumor, and blood analysis showed anemia. The patient was treated by radical cystectomy with ileal conduit construction. An ileal conduit was constructed in the left lower abdomen; it was impossible to construct in the right lower abdomen because of the abdominal wall scar hernia due to the past open surgery.

Conclusion: We herein reported a patient who underwent ileal conduit for urinary diversion on the left side of low abdominal wall.
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http://dx.doi.org/10.1002/iju5.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292152PMC
March 2020

Effect of Transcatheter Aortic Valve Implantation on the Immune Response Associated With Surgical Aortic Valve Replacement.

Am J Cardiol 2020 08 14;128:35-44. Epub 2020 May 14.

Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

The immune response after transcatheter aortic valve implantation (TAVI) in comparison to that after surgical aortic valve replacement (SAVR) remains to be fully elucidated. In a 2-part study, we assessed laboratory data obtained before, immediately after, and 24 and 48 hours after SAVR (128 patients; age ≥80 [mean 82] years) or transfemoral TAVI (102 patients; age ≥80 [mean 86] years) performed for aortic stenosis. In-hospital mortalities were similar (3% vs 0%), but leukocyte counts and aspartate aminotransferase and creatine kinas concentrations were decreased immediately and 24 hours after surgery (all, p <0.001). We performed cytokine profiling in a SAVR group (11 patients; mean age, 77 years) and transfemoral TAVI group (12 patients; mean age, 84 years). By measuring normalized concentrations of 71 cytokines at 3 time points, we found a significant difference (defined as fold change >1.7 and p <0.05 [by Mann-Whitney U-test]) in 23 cytokines. The differentially expressed cytokines fell into 3 hierarchical clusters: cluster A (high increase after SAVR and suppressed increase after TAVI only immediately after surgery [CCL2, CCL4, and 2 others]), cluster B (high increase after SAVR and suppressed increase after TAVI at 2 time points [IL-1Ra, IL-6, IL-8, IL-10, and 5 others]), and cluster C (various patterns [TRAIL, CCL11, and 8 others]). Gene enrichment analysis identified multiple pathways associated with the inflammatory responses in SAVR and altered responses in TAVI, including cellular responses to tumor necrosis factor (p = 0.0035) and interleukin-1 (p = 0.0062). In conclusion, a robust inflammatory response follows SAVR, and a comparatively attenuated response follows TAVI.
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http://dx.doi.org/10.1016/j.amjcard.2020.04.037DOI Listing
August 2020

Prognostic factors influencing overall survival in de novo oligometastatic prostate cancer patients.

Prostate 2020 08 5;80(11):850-858. Epub 2020 Jun 5.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Oligometastatic cancer has been suggested as an intermediate state between localized disease and wide-ranging metastases. The clinical significance of local treatment in oligometastatic prostate cancer (PCa) has been a recent topic of interest. However, standard definitions of oligometastasis are lacking. Here we studied risk factors among Japanese de novo oligometastatic patients with PCa.

Methods: We retrospectively assessed clinical data from 264 patients, including locally advanced (T3 or T4N0M0) cancer, lymph-node-positive cancer (T N1M0), and cancer with ≤10 bone metastases. All patients received androgen deprivation therapy only. The number of bone metastases and clinical factors were evaluated in association with overall survival (OS) and progression-free survival (PFS). The Mann-Whitney U test, Cox proportional hazard models, and Kaplan-Meier methods were used as statistical analyses.

Results: Median age, PSA at baseline and OS were 74 years, 55.2 ng/mL, and 129.0 months, respectively. The cutoff for the number of bone metastases having the greatest impact on OS was ≥3 (hazard ratio [HR]: 2.67; P = .0001). In multivariate analysis, non-regional lymph node (LN) metastases (HR: 2.15; P = .0222), ISUP grade group (GG) 5 (HR: 2.04; P = .0186) and ≥3 bone metastases (HR: 1.82; P = .0390) were independent predictors of OS. In risk classification based on these factors, OS and PFS were significantly classifiable into poor (2-3 factors), intermediate (1 factor), and good (no factors) risk groups (P < .0001).

Conclusion: Not only the number of bone metastases, but also non-regional LN metastases predict OS in patients with de novo oligometastatic PCa.
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http://dx.doi.org/10.1002/pros.24016DOI Listing
August 2020

Prognostic value of an inflammatory index for patients with metastatic castration-resistant prostate cancer.

Prostate 2020 05 5;80(7):559-569. Epub 2020 Mar 5.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: The inflammatory process has been reported to be involved in the formation and progression of various types of cancer. Recently, a peripheral inflammatory index, combining the derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and the lactate dehydrogenase (LDH) level, was proposed as a useful prognostic marker in advanced nonsmall cell lung cancer. The prognostic value of inflammatory markers in prostate cancer has not been established. We aimed to validate the prognostic significance of this peripheral inflammatory index in metastatic castration-resistant prostate cancer (mCRPC).

Methods: Clinical data of 196 mCRPC patients were retrospectively collected from multiple institutions. Clinical factors and inflammatory markers at the development of CRPC, including white blood cell count, absolute neutrophil count, dNLR, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, C-reactive protein (CRP), and LDH levels, were evaluated. The patients were classified into three groups based on the inflammatory index: Good (low dNLR and LDH), Intermediate (high dNLR or LDH), and Poor (high dNLR and LDH). Overall survival (OS) and cancer-specific survival after CRPC were analyzed using Cox proportional hazard models and Kaplan-Meier methods.

Results: The median age and baseline prostate-specific antigen level were 75 years and 397.15 ng/mL, respectively. On multivariate analysis, dNLR (≥1.51; hazard ratio [HR] = 1.624; P = .0173), LDH (≥upper limit of normal; HR = 2.065; P = .0004), alkaline phosphatase (≥310 U/L; HR = 2.546; P < .0001), and positive N stage (HR = 1.621; P = .048) were associated with poor OS after CRPC, whereas other inflammatory markers including the NLR were not. The Good inflammatory index group showed significantly longer OS after CRPC compared to the Intermediate and Poor groups, with median survivals of 46.2, 28.9, and 16.6 months, respectively.

Conclusions: The novel inflammatory index combining dNLR and LDH was a useful prognostic parameter in patients with mCRPC. Our analysis suggested that dNLR emerged as a more valuable prognostic marker than NLR.
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http://dx.doi.org/10.1002/pros.23969DOI Listing
May 2020

Soft coagulation in robot-assisted partial nephrectomy without renorrhaphy: Comparison with standard suture.

Int J Urol 2020 Apr 8;27(4):352-354. Epub 2020 Feb 8.

Department of Urology, Chiba University Hospital, Chiba, Japan.

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http://dx.doi.org/10.1111/iju.14195DOI Listing
April 2020

How many bone metastases may be defined as high-volume metastatic prostate cancer in Asians: A retrospective multicenter cohort study.

Prostate 2020 04 3;80(5):432-440. Epub 2020 Feb 3.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Recent landmark randomized trials (CHAARTED and LATITUDE studies) have highlighted potent upfront therapy for "high-volume" and "high-risk" metastatic castration-naïve prostate cancer (mCNPC). However, treatment response shows racial differences. We aimed to propose a novel definition for "high-volume" prostate cancer in Asians.

Methods: We retrospectively pursued 426 patients with de novo mCNPC from multiple institutions between 1999 and 2017. All patients received androgen deprivation therapy alone as initial treatment. We evaluated the number of bone metastases at diagnosis to clarify the clinical significance for progression-free survival and overall survival (OS). Statistical analyses were conducted using the Mann-Whitney U test, Cox proportional hazard models, and Kaplan-Meier methods.

Results: Median age and prostate-specific antigen level were 73 years and 266.2 ng/ml, respectively. Median OS was 55.5 months in patients who met the CHAARTED high criteria (vs 33.1 months in the trial). We evaluated 5 thresholds in the number of bone metastases (≥4, ≥6, ≥11, ≥16, and ≥21) to investigate the prognostic values. Patients with ≥11 bone metastases showed the highest HR for OS (2.766). Patients with 11 to 20 bone metastases had a significantly shorter OS than those with ≤10 metastases (P = .0001). We, therefore, proposed modified CHAARTED and LATITUDE high criteria (extending bone metastases ≥11). In multivariate analysis, the modified criteria were the only independent prognostic factors for OS (P = .0272 and P = .042, respectively). Conversely, no significant differences in OS were seen between patients with 1 to 3 bone metastases and 4 to 10 (P = .7513).

Conclusion: Our exploratory study suggested ≥11 bone metastases as a suitable definition for "high-volume" prostate cancer in Asians. A larger, prospective study is warranted to verify our findings.
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http://dx.doi.org/10.1002/pros.23958DOI Listing
April 2020

Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma.

Sci Rep 2020 Jan 28;10(1):1292. Epub 2020 Jan 28.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.
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http://dx.doi.org/10.1038/s41598-020-58136-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987139PMC
January 2020

Determinants of prolonged hospitalization in patients who underwent trans-femoral transcatheter aortic valve implantation.

Postepy Kardiol Interwencyjnej 2019 8;15(4):431-438. Epub 2019 Dec 8.

Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

Introduction: Transcatheter aortic valve implantation (TAVI) has grown to be an alternative treatment for severe symptomatic aortic valve stenosis (AS) in elderly patients. Although TAVI is a less invasive surgery than surgical aortic valve replacement, some patients may require prolonged hospitalization.

Aim: To find the determinants of prolonged hospitalization in patients who underwent trans-femoral TAVI.

Material And Methods: A total of 94 AS patients who underwent trans-femoral TAVI were included as the final study population, and divided into the conventional hospitalization group (≤ 21 days) ( = 74) and prolonged hospitalization group (> 21 days) ( = 20). We compared clinical characteristics between the two groups, and multivariate logistic regression analysis was performed to find the determinants of prolonged hospitalization.

Results: In multivariate logistic regression analysis, moderate or severe mitral regurgitation (OR = 4.49, 95% CI: 1.16-17.47, = 0.03), taking statins or angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARB) on admission (statins: OR = 0.13, 95% CI: 0.02-0.71, = 0.02, ACE inhibitors/ARB: OR = 0.25, 95% CI: 0.06-0.96, = 0.04), estimated glomerular filtration rate (eGFR) (per 15 ml/min/1.73 m incremental) (OR = 0.49, 95% CI: 0.26-0.90, = 0.02) and current chopsticks user (OR = 0.05, 95% CI: 0.01-0.41, < 0.01) were significantly associated with prolonged hospitalization.

Conclusions: Moderate or severe mitral regurgitation was significantly associated with prolonged hospitalization, while current chopsticks user, eGFR (per 15 ml/min/1.73 m incremental), taking ACE inhibitors/ARB or statins before the procedure were inversely associated with prolonged hospitalization in patients who underwent trans-femoral TAVI.
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http://dx.doi.org/10.5114/aic.2019.90217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956457PMC
December 2019

Higher serum testosterone levels predict poor prognosis in castration-resistant prostate cancer patients treated with docetaxel.

Prostate 2020 02 9;80(3):247-255. Epub 2019 Dec 9.

Department of Urology, Chiba University Hospital, Chiba, Japan.

Background: The role of testosterone as a prognostic factor for castration-resistant prostate cancer treated with docetaxel in Japan was investigated.

Methods: A total of 164 patients with castration-resistant prostate cancer who received docetaxel treatment at Chiba University Hospital and an affiliated hospital were retrospectively analyzed. Testosterone and other clinical factors at the start of docetaxel treatment were evaluated with respect to overall survival and progression-free survival.

Results: Of the 164 patients, 69 had high-volume tumors. The median prostatic-specific antigen was 27.0 ng/mL. The median testosterone was 13.0 ng/dL. The rates of bone and visceral metastases were 80.1% and 8.8%, respectively. For progression-free survival, testosterone ≥13 ng/dL was an independent prognostic factor only on univariate analysis (hazard ratio, 1.81; P = .0108). For overall survival, testosterone ≥ 1.3 ng/dL (hazard ratio, 3.37; P < .0001), high volume (hazard ratio, 3.06; P = .0009), and prostate-specific antigen ≥ 27.0 ng/mL (hazard ratio, 2.75; P = .0013) were independent prognostic factors on multivariate analysis. When assessing related clinical factors, higher serum testosterone was associated with visceral metastasis, high volume, and prostate-specific antigen. Based on three prognostic factors (testosterone, high volume, prostate-specific antigen), a risk classification was developed. The high-risk group (3 risk factors) showed a significantly shorter overall survival compared to the moderate-risk (2 risk factors) and low-risk (0-1 risk factor) groups (P < .0001).

Conclusions: The present study identified higher serum testosterone (≥13 ng/dL) as a significant prognostic factor in castration-resistant prostate cancer patients treated with docetaxel therapy.
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http://dx.doi.org/10.1002/pros.23938DOI Listing
February 2020

Characterization of the expression of LAT1 as a prognostic indicator and a therapeutic target in renal cell carcinoma.

Sci Rep 2019 11 20;9(1):16776. Epub 2019 Nov 20.

Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan.

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.
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http://dx.doi.org/10.1038/s41598-019-53397-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868143PMC
November 2019

Impact of post-void residual urine volume on intravesical recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma.

Int J Urol 2019 12 14;26(12):1106-1112. Epub 2019 Sep 14.

Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Objective: To examine the impact of post-void residual urine volume on the risk of postoperative recurrence of intravesical carcinoma in patients with upper urinary tract urothelial carcinoma undergoing nephroureterectomy.

Methods: We retrospectively reviewed the data of 81 patients who were admitted to Chiba University Graduate School of Medicine Hospital and underwent nephroureterectomy for upper urinary tract urothelial carcinoma without bladder carcinoma. We assessed the predictive factors for intravesical recurrence after nephroureterectomy in all patients. Next, we compared patients with and without a residual urine volume using propensity score-matching analysis. The presence of a residual urine volume was defined as ≥30 mL.

Results: The median follow-up period among all patients was 48 months. The presence of pyuria and a residual urine volume were associated with bladder recurrence in the multivariate analysis. A total of 19 patients each were selected after matching, and we confirmed a significant difference between the presence and absence of a residual urine volume (P = 0.0291). The 2-year postoperative recurrence-free rate of patients with and without a residual urine volume was 32% and 82%, respectively.

Conclusions: This is the first study to evaluate the post-void residual urine volume and intravesical recurrence rate after nephroureterectomy for upper urinary tract urothelial carcinoma. The presence of residual urine might be a risk factor for postoperative recurrence of intravesical carcinoma.
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http://dx.doi.org/10.1111/iju.14103DOI Listing
December 2019

Total Synthesis of 1-Hydroxytaxinine.

Angew Chem Int Ed Engl 2019 08 25;58(35):12159-12163. Epub 2019 Jul 25.

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

1-Hydroxytaxinine (1) is a cytotoxic taxane diterpenoid. Its central eight-membered B-ring possesses four oxygen-functionalized centers (C1, C2, C9, and C10) and two quaternary carbon centers (C8 and C15), and is fused with six-membered A- and C-rings. The densely functionalized and intricately fused structure of 1 makes it a highly challenging synthetic target. Reported here is an efficient radical-based strategy for assembling 1 from A- and C-ring fragments. The A-ring bearing an α-alkoxyacyl telluride moiety underwent intermolecular coupling with the C-ring fragment by a Et B/O -promoted decarbonylative radical formation. After construction of the C8-quaternary stereocenter, a pinacol coupling reaction using a low-valent titanium reagent formed the B-ring with stereoselective installation of the C1,C2-diol. Subsequent manipulations at the A- and C-rings furnished 1 in 26 total steps.
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http://dx.doi.org/10.1002/anie.201906872DOI Listing
August 2019

Intravesical irrigation might prevent bladder recurrence in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma.

Int J Urol 2019 08 12;26(8):791-796. Epub 2019 May 12.

Department of Urology, Chiba University Hospital, Chiba, Japan.

Objectives: To examine the effectiveness of intravesical irrigation with physiological saline solution or distilled water for the prevention of bladder recurrence in patients undergoing laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma.

Methods: This retrospective study involved 109 upper urinary tract urothelial carcinoma patients who underwent laparoscopic nephroureterectomy, and were evaluated at Chiba University Hospital and Yokohama Rosai Hospital between 2001 and 2018. We investigated the outcomes and analyzed various clinical factors including with or without intravesical irrigation related to bladder carcinoma recurrence after surgery. Physiological saline solution or distilled water was used for irrigation, which was carried out only during surgery.

Results: The median follow-up period after surgery was 26.1 months. Bladder recurrence was confirmed within 2 years for 45 of the 109 patients in the present study. Irrigation was carried out for 48 cases (distilled water, 26 patients; physiological saline solution, 22 patients). Tumor grade (G1-2 vs G3; P = 0.05) and intravesical irrigation (yes vs no; P = 0.0058) were related to bladder recurrence on univariate analyses. On multivariate analyses, intravesical irrigation was the independent factor involved in the prevention of bladder recurrence (P = 0.0051). Comparison between the irrigation and non-irrigation groups showed that bladder recurrence rates were significantly lower in the irrigation group (irrigation group vs non-irrigation group: 25.0% vs 52.5%, P = 0.0066). There was no significant difference in the recurrence rate between the two solutions used for irrigation.

Conclusions: Intravesical irrigation during surgery of upper urinary tract urothelial carcinoma might decrease postoperative bladder recurrence rates.
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http://dx.doi.org/10.1111/iju.14014DOI Listing
August 2019

Contralateral adrenal width predicts the duration of prolonged post-surgical steroid replacement for subclinical Cushing syndrome.

Int J Urol 2018 06 12;25(6):583-588. Epub 2018 Apr 12.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

Objectives: To identify pre-treatment factors affecting the duration of post-surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome.

Methods: The present retrospective analysis included 64 patients who underwent unilateral laparoscopic adrenalectomy for subclinical Cushing syndrome. Adrenal tumor and contralateral adrenal sizes together with various clinical factors were studied in association with the duration of post-surgical steroid replacement. Adrenal tumor and contralateral adrenal size were measured at the level of the maximum transverse plane of the adrenal glands using computed tomography scan or magnetic resonance imaging. Cox's proportional hazards model was used for the statistical analysis.

Results: All 64 patients were treated with post-surgical steroid replacement after adrenalectomy. The median duration of the steroid treatment was 6 months. When assessing the duration of post-surgical steroid replacement, contralateral adrenal volume <0.745 cm , contralateral adrenal width <6.15 mm and serum cortisol after a 1-mg dexamethasone suppression test >2.65 μg/dL were significant predictors of prolonged post-surgical steroid treatment on univariate analysis. On multivariate analysis, contralateral adrenal width <6.15 mm was the only independent predictive factor for the prolonged post-surgical steroid replacement.

Conclusions: Contralateral adrenal width seems to represent a significant predictive factor for the duration of post-surgical steroid replacement in subclinical Cushing syndrome patients. Pre-surgical assessment of image findings might help clinicians determine the total duration of steroid therapy after adrenalectomy.
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http://dx.doi.org/10.1111/iju.13566DOI Listing
June 2018

Biparametric Prostate Imaging Reporting and Data System version2 and International Society of Urological Pathology Grade Predict Biochemical Recurrence after Radical Prostatectomy.

Clin Genitourin Cancer 2018 08 24;16(4):e817-e829. Epub 2018 Feb 24.

Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: We retrospectively assessed the clinical significance of the Prostate Imaging Reporting and Data System (PI-RADS), version 2, criteria based on biparametric magnetic resonance imaging (bp-MRI), together with the International Society of Urological Pathology (ISUP) grade, for predicting biochemical recurrence (BCR) after radical prostatectomy.

Materials And Methods: The data from 126 patients who had undergone radical prostatectomy were retrospectively analyzed. The prognostic significance of the PI-RADS v2 score based on bp-MRI was assessed with other clinical factors, including the ISUP grade. We defined a positive PI-RADS and ISUP score as ≥ 4 and ≥ 3, respectively. Statistical analysis was performed using Cox proportional hazard models, logistic regression analysis, and the Kaplan-Meier method.

Results: The median age and median prostate-specific antigen level were 66 years and 7.96 ng/mL, respectively. The number of positive PI-RADS scores was 106 (84.1%) and the number of positive ISUP grade scores was 71 (56.3%). PI-RADS ≥ 4 (P = .0031) and ISUP ≥ 3 (P = .070) were the 2 independent prognostic factors predictive of BCR. A positive PI-RADS score was related to tumor volume (P = .014), and a positive ISUP score was related to prostate-specific antigen level (P = .043), extraprostatic extension (P = .029), and Gleason upgrading (P < .0001). After stratifying patients into risk groups according to PI-RADS and ISUP positivity, the poor-risk group (PI-RADS and ISUP grade positive) showed significantly worse BCR-free survival compared with that of the favorable- and intermediate-risk groups (P < .0001), with a median survival difference of 21 months.

Conclusion: Biparametric PI-RADS v2 and ISUP grade criteria predicted for BCR after radical prostatectomy. PI-RADS v2 combined with the ISUP grade might be helpful in choosing the treatment modality of patients with localized prostate cancer.
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http://dx.doi.org/10.1016/j.clgc.2018.02.011DOI Listing
August 2018

Duration of androgen deprivation therapy and nadir of testosterone at 20 ng/dL predict testosterone recovery to supracastrate level in prostate cancer patients who received external beam radiotherapy.

Int J Urol 2018 04 11;25(4):352-358. Epub 2018 Jan 11.

Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.

Objectives: To determine the predictors of testosterone recovery after termination of androgen deprivation therapy in high/intermediate-risk prostate cancer patients receiving external beam radiation therapy with neoadjuvant and adjuvant androgen deprivation therapy.

Methods: A total of 82 patients who underwent external beam radiation therapy with androgen deprivation therapy for prostate cancer were retrospectively analyzed. Serum testosterone levels after androgen deprivation therapy terminations were studied. Cox proportional hazard models and the Kaplan-Meier method were used for statistical analysis.

Results: Median age, baseline testosterone, nadir testosterone and duration of androgen deprivation therapy were 73 years, 456 ng/dL, 16 ng/dL and 26 months, respectively. Androgen deprivation therapy duration of 33 months (hazard ratio 0.13; P = 0.0018), nadir testosterone of 20 ng/dL (hazard ratio 0.35; P = 0.0112) and testosterone >50 ng/dL at 6 months after androgen deprivation therapy termination (hazard ratio 0.21; P = 0.0075) were significantly associated with testosterone recovery to normal levels (200 ng/dL) on multivariate analysis. Androgen deprivation therapy duration of 33 months (hazard ratio 0.31; P = 0.0023) and nadir testosterone of 20 ng/dL (hazard ratio 0.38; P = 0.0012) were significantly associated with testosterone recovery to the supracastrate level (50 ng/dL) on multivariate analysis. After dividing patients into three risk groups, the rate of testosterone recovery to the normal level after 2 years of androgen deprivation therapy termination was 100% in the low-risk group versus 20.8% in the high-risk group (P < 0.0001); the rate of testosterone recovery to the supracastrate level was 100% in the low-risk group versus 51.5% in the high-risk group (P < 0.0001).

Conclusions: Duration of androgen deprivation therapy and achievement of nadir testosterone 20 ng/dL both predict testosterone recovery to the supracastrate level in prostate cancer patients undergoing external beam radiation therapy with androgen deprivation therapy.
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http://dx.doi.org/10.1111/iju.13521DOI Listing
April 2018
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